The macrolide compound of formula (I), below shown, (8E,12E,14E)-7-{(4-cycloheptylpiperazin-1-yl)carbonyl}oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide, as well as pharmaceutically acceptable salts and hydrates thereof, suppresses a vascular endothelial growth factor (VEGF) production, suppresses angiogenesis in cancer, and strongly suppresses solid tumor cell proliferation in in vivo experiments. Based on such effects, this compound has been reported to be particularly useful as a prophylactic or therapeutic agent for solid tumors and the like (see, for example, International Disclosure No. WO 03/099813).
General mention is made in WO 03/099813 that a series of 12-membered ring macrolide compounds and hydrates thereof are capable of forming crystal polymorphs. However, the compound of formula (I), which is the compound of Example 45 in WO 03/099813, is mentioned therein as being obtained as an oily substance; no disclosure whatsoever is made of the properties of a crystalline or amorphous solid form thereof. Nor has any disclosure been made of a process for preparing such a solid or of a pharmaceutical composition containing such a solid.
WO 03/099813 also discloses in detail a process for synthesizing the compound of formula (I). However, since post-treatment in this synthetic process is complex and purification by column chromatography is required in each step, there are aspects to the process that make it poorly conducive for the commercial production of a bulk medicament for pharmaceutical manufacture. Moreover, because the compound of formula (I) thus obtained has the properties of an oily substance, it has a poor uniformity and is of irregular purity, as a result of which it has not always been of sufficient quality for use as a bulk medicament for pharmaceutical manufacture.
In addition, the process described in WO 03/099813 requires the use of dichloromethane as the reaction solvent in synthesis of the compound of formula (I) and as the eluting solvent during column purification. Yet, dichloromethane, owing to its effects on the human body, is classed under UN Hazard Class 6.1 (Toxic Substances), and is categorized under the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Quality Guideline Q3C (Impurities: Residual Solvents) as Class 2 (Solvents whose residual quantities in pharmaceutical products should be limited). Furthermore, in Japan, there are concerns over how this chemical is handled; for example, upper limit values for dichloromethane have been set as environmental standards for atmospheric pollution and water pollution.